Muscle weakness is common among patients who develop acute lung injury (ALI). The weakness is rapid in onset and persists for at least two years following hospitalization. Weakness, not impaired lung function, appears to account for the morbidity associated with survivors of ALI. The mechanisms for this weakness are poorly understood. Our murine model of ALI using intratracheal lipopolysaccharide produces profound lung injury and muscle weight loss. Our preliminary data show that ALI mice develop skeletal muscle atrophy, measured by histological changes and by activation of skeletal muscle specific protein degradation pathways. To define the molecular mechanisms of muscle wasting in ALI mice, we propose the following plan: Specific Aim 1 will define the structural and biochemical phenotypes and functional consequences of skeletal muscle wasting in ALI mice. We plan to describe the functional and histologic phenotype of ALI mice, explore protein synthesis versus degradation, and elucidate potential mechanisms of muscle atrophy in these animals. We will determine fiber size and type, and measure force of both intact and explanted skeletal muscles. We will use ex vivo muscle preparations, RT-qPCR, and Western blot analysis to explore molecular pathways of muscle atrophy in these mice. Because ALI mice also have reduced voluntary food intake, the goal of Specific Aim 2 will be to define the effects that reduced food intake plays on the skeletal muscle wasting seen in ALI mice. We plan to rigorously control for the reduction in food intake in ALI mice both by pair-feeding the controls and by enforced feeding of ALI mice through gastrostomy tubes. We will also investigate whether the apparent suppression of appetite in these animals is indicative of a state of cachexia and how this state may alter muscle wasting and impair the recovery process. The emphasis of this proposal is on the mechanisms of muscle wasting in ALI and how decreased intake of food may affect this process. Muscle wasting in ALI addresses a significant health issue and a relatively unexplored area of investigational science. Our ultimate goal is to develop interventions or therapies which would alleviate the morbidity of muscle weakness associated with ALI. LAY ABSTRACT: Survivors of acute lung injury (ALI) experience severe muscle weakness that is rapid in onset and persists for at least two years following hospitalization. The etiology of this weakness is not understood. In our model of ALI, mice undergo profound weight loss and have injured muscles. We propose to describe the type and extent of muscle injury and determine how this process occurs. Our ultimate goal is to develop an understanding of the process that will lead to rational and specific treatments to prevent and reverse ALl-induced muscle injury.